This invention relates to novel lactams substituted by cyclic succinates having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review see Dennis J.Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to its deposition in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed xcex2 amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Axcex2 is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, xcex1 secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and xcex3 secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other xcex2 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of xcex2 APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3 secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or xcex3 secretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
PCT publication number WO 96/29313 discloses the general formula: 
covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.
Compounds of general formula: 
are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.
European Patent Application number EP 0652009A1 relates to the general formula: 
and discloses compounds that are protease inhibitors that inhibit Axcex2 production.
U.S. Pat. No. 5,703,129 discloses the general formula: 
which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Axcex2 production and are useful in the treatment of Alzheimer""s disease.
Copending, commonly assigned U.S. patent application Ser. No. 09/370089 filed Aug. 7, 1999 (equivalent to international application PCT US99/17717) discloses lactams of general formula: 
wherein the lactam ring B is substituted by succinamide and a carbocyclic, aryl, or heteroaryl group. These compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R3 and R3a are combined to form a carbocyclic or heterocyclic ring, R5, R5a, R6, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Axcex2.
Thus, in a first embodiment, the present invention provides a novel compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is xe2x80x94NR1R2;
R1 is H, C1-C4 alkyl, phenyl, benzyl, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)methyl-;
R2 is H, C1-C4 alkyl, OH, C1-C4 alkoxy, phenyl, benzyl, C3-C6 cycloalkyl, or (C3-C6 cycloalkyl)methyl-;
R3 and R3a may be combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94, and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents: on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
alternatively, R3 is H; C1-C6 alkyl substituted with 0-3 R4; C2-C6 alkenyl substituted with 0-3 R4; or C2-C6 alkynyl substituted with 0-3 R4; and R3a is H, C1-C6 alkyl, or C2-C6 alkenyl;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94, C3-C6 carbocycle, aryl, and a 5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R5 is H, C1-C6 alkoxy;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with a 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5a is H, C1-C4 alkyl, or C2-C4 alkenyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
alternatively, R5 and R5a may be combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94, and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R5c;
provided at least:
1) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; or
2) R5 and R5a are combined to form a 3-8 membered carbocyclic moiety; or
3) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety and R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, aryl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is a 6, 7, or 8 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains an additional heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R10)xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R10b; or a 5-6 membered heterocycle substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3,
C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond or xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-S, and aryl substituted with 0-3 R12c;
R12c, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, and C1-C3 haloalkyl;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 6 membered heterocyclic ring;
R19b, at each occurrence, is independently is H or C1-C4 alkyl;
R20 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17; C1-C6 alkyl optionally substituted with 0-3 R20a; or C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;
R20b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
[2] In a preferred embodiment the present invention provides for a compound of Formula (II): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 and R3a may be combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated; and
R5 and R5a may be combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
provided at least:
1) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; or
2) R5 and R5a are combined to form a 3-8 membered carbocyclic moiety; or
3) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety and R5 and R5a are combined to form a 3-8 membered carbocyclic moiety.
[3] In a preferred embodiment the present invention provides for a compound of Formula (II) wherein:
R3 and R3a may be combined to form a 3-8 membered carbocyclic moiety selected. from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl;
alternatively, R3 and R3a are independently selected from the group H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
R5 is H;
C1-C4 alkyl substituted with 0-1 R5b;
C2-C4 alkenyl substituted with 0-1 R5b;
C2-C4 alkynyl substituted with 0-1 R5b;
R5a is H, C1-C4 alkyl, or C2-C4 alkenyl;
R5b is selected from:
H, methyl, ethyl, propyl, butyl, CF3, Cl, F, NR15R16, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
alternatively, R5 and R5a may be combined to form a 3-8 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl;
provided at least:
1) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; or
2) R5 and R5a are combined to form a 3-8 membered carbocyclic moiety; or
3) R3 and R3a are combined to form a 3-8 membered carbocyclic moiety and R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
Ring B is a 7 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains an additional heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R10)xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 tc 6 membered heteroaryl fused radical is substituted with 0-3 R13;
additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13.
[4] In a preferred embodiment the present invention provides for a compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Q is xe2x80x94NR1R2;
R1 is H, methyl, ethyl, propyl, butyl, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobut-ylmethyl, cyclopentylmethyl, or cyclohexylmethyl;
R2 is H, methyl, ethyl, propyl, butyl, OH, methoxy, ethoxy, propoxy, phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylpentyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl;
R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety may optionally contain a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R20)xe2x80x94, and
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R4 substituents, on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94, C3-C6 carbocycle, aryl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur;
R5 is H, C1-C6 alkoxy;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5a is H, C1-C4 alkyl, or C2-C4 alkenyl;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, R15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R6 is H;
C1-C6 alkyl substituted with 0-3 R6a;
C3-C10 carbocycle substituted with 0-3 R6b; or
C6-C10 aryl substituted with 0-3 R6b;
R6a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, aryl or CF3;
R6b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is a 7 membered lactam,
wherein the lactam is saturated, partially saturated or unsaturated;
wherein each additional lactam carbon is substituted with 0-2 R11; and,
optionally, the lactam contains an additional heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94Nxe2x95x90, xe2x80x94NHxe2x80x94, and xe2x80x94N(R10)xe2x80x94;
additionally, two R11 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R13;
additionally, two R11 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R13;
additionally, two R11 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R13;
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R10b; or a 5-6 membered heterocycle substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond or xe2x80x94(CR8R8a)pxe2x80x94;
p is 0, 1, 2, 3, or 4;
R8 and R8a, at each occurrence, are independently selected from H, F, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C8 cycloalkyl;
X is a bond;
C6-C10 aryl substituted with 0-3 RXb;
C3-C10 carbocycle substituted with 0-3 RXb; or
5 to 10 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 halothioalkoxy;
Y is a bond or xe2x80x94(CR9R9a)txe2x80x94Vxe2x80x94(CR9R9a)uxe2x80x94;
t is 0, 1, or 2;
u is 0, 1, or 2;
R9 and R9a, at each occurrence, are independently selected from H, F, C1-C6 alkyl or C3-C8 cycloalkyl;
V is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N (Rl9)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-S, and aryl substituted with 0-3 R12c;
R12c, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, and C1-C3 haloalkyl;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 6 membered heterocyclic ring;
R9b, at each occurrence, is independently is H or C1-C4 alkyl;
R20 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R20a; or
C6-C10 aryl substituted with 0-4 R20b;
R20a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, or aryl substituted with 0-4 R20b;;
R20b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
[5] In another preferred embodiment the present invention provides for a compound of Formula (Ia): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents; on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents; on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substituted with 0-3 R23;
additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94, C3-C6 carbocycle, aryl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur; and
R5 is H, C1-C4 alkoxy;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with. 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R6 is H, methyl, or ethyl;
Ring B is selected from: 
R10 is H, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, S(xe2x95x90O)2R17;
C1-C6 alkyl optionally substituted with 0-3 R10a;
C6-C10 aryl substituted with 0-4 R10b;
C3-C10 carbocycle substituted with 0-3 R10b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R10b;
R10a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3, aryl substituted with 0-4 R10b; or a 5-6 membered heterocycle substituted with 0-4 R10b;
R10b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NFR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substitutes with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, R15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond or xe2x80x94(CH2)pxe2x80x94;
p is 1 or 2;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 carbocycle substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, and C1-C3 halothioalkoxy;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with. 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C3-C6 cycloalkyl, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 halcoalkyl-S, and aryl substituted with 0-3 R12c;
R12c, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, and C1-C3 haloalkyl;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl;
additionally, R18 and R19, when substituents on the same atom, may be combined to form a 3 to 6 membered heterocyclic ring selected from pyrrolyl, imidazolyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl;
R19b, at each occurrence, is independently is H or C1-C4 alkyl; and
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
[6] In another preferred embodiment the present invention provides for a compound of Formula (Ib): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-4 R4;
additionally, two R4 substituents on adjacent atoms may be combined to form a benzo fused radical; wherein said benzo fused radical is substituted with 0-4 R23;
additionally, two R4 substituents on adjacent atoms may be combined to form a 5 to 6 membered heteroaryl fused radical, wherein said 5 to 6 membered heteroaryl fused radical comprises 1 or 2 heteroatoms selected from N, O, and S; wherein said 5 to 6 membered heteroaryl fused radical is substitute d with 0-3 R23;
additionally, two R4 substituents on the same or adjacent carbon atoms may be combined to form a C3-C6 carbocycle substituted with 0-3 R23;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C6 alkenyl, alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94, C3xe2x80x94C6 carbocycle, aryl, and a
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur; and
R5 is H;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, C1-C4 alkoxy, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR18R19, C(xe2x95x90O)R17, C(xe2x95x90O)OR17, C(xe2x95x90O)NR18R19, S(xe2x95x90O)2NR18R19, CF3;
C1-C6 alkyl optionally substituted with 0-3 R11a;
C6-C10 aryl substituted with 0-3 R11b;
C3-C10 carbocycle substituted with 0-3 R11b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R11b;
R11a, at each occurrence, is independently selected from H, C1-C6 alkyl, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16, CF3;
phenyl substituted with 0-3 R11b;
C3-C6 cycloalkyl substituted with 0-3 R11b; and
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a;
C2-C6 alkynyl substituted with 0-3 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R17 is H, C1-C6 alkyl, C2-C6 alkoxyalkyl, aryl substituted by 0-4 R17a, or xe2x80x94CH2-aryl substituted by 0-4 R17a;
R17a is H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, xe2x80x94OH, F, Cl, Br, I, CF3, OCF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94NH2, xe2x80x94N(CH3)2, or C1-C4 haloalkyl;
R18 at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl; and
R23, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3.
[7] In another preferred embodiment the present invention provides for a compound of Formula (Ib):
R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R4;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 is H;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C7 carbocycle substituted with 0-3 R11b; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b, wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C8 alkyl substituted with 0-3 R12a;
C2-C6 alkenyl substituted with 0-3 R12a; or
C2-C6 alkynyl substituted with 0-3 R12a;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, xe2x80x94C(xe2x95x90O)NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkyl-Sxe2x80x94, C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; and wherein said 5 to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrezolyl, imidazolyl, oxazolyl, isoxazolyl, tet-razolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)-S(xe2x95x90O2xe2x80x94;
R16, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O2xe2x80x94; and
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl., butyl, phenyl, benzyl, and phenethyl.
[8] In another preferred embodiment the present invention provides for a compound of Formula (Ib):
R3 and R3a are combined to form a 3-6 membered carbocyclic moiety;
wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-6 membered cearbocyclic moiety is substituted with 0-2 R4;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, xe2x80x94OCF3, and xe2x80x94SCF3;
R5 is H;
C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-3 R5b; or
C2-C4 alkynyl substituted with 0-3 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O;
C3-C6 carbocycle substituted with 0-3 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C7 carbocycle substituted with 0-3 R11b; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C1-C4 alkyl substituted with 0-3 R12a;
C2-C4 alkenyl substituted with 0-3 R12a; or
C2-C4 alkynyl substituted with 0-3 R12a;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, and benzyl;
R16, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(xe2x95x90O)xe2x80x94, ethyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, and ethyl-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
[9] In another preferred embodiment the present invention provides for a compound of Formula (Ib):
R3 and R3a are combined to form a 3-6 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl; wherein said 3-6 membered carbocyclic moiety is substituted with 0-1 R4;
R4 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and xe2x80x94OCF3;
R5 is C1-C4 alkyl substituted with 0-1 R5b;
C2-C4 alkenyl substituted with 0-1 R5b;
C2-C4 alkynyl substituted with 0-1 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, xe2x95x90O;
C3-C6 carbocycle substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R5c; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acestyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
cyclohexyl substituted with 0-3 R11b;
cycloheptyl substituted with 0-3 R11b;
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond;
X is a bond;
Y is a bond;
Z is H;
C3-C4 alkyl substituted with 0-1 R12a;
C2-C4 alkenyl substituted with 0-1 R12a; or
C2-C4 alkynyl substituted with 0-1 R12a;
R12a, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O) CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
[10] In another preferred embodiment the present invention provides for a compound of Formula (Ib):
R3 and R3a are combined to form cyclobutyl, cyclopentyl, cyclopentenyl, or cyclohexyl;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CH2CF3, xe2x80x94CH2CH2CH2CF3, xe2x80x94CH2CH2CH2CH2CF3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, cis-CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CH(C6H5), xe2x80x94CH2CHxe2x95x90C(CH3)2, cis-CH2CHxe2x95x90CHCH2CH3, trans-CH2CHxe2x95x90CHCH2CH3, cis-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CH2CHxe2x95x90CH(CH3), trans-CH2CHxe2x95x90CHCH2(C6H5), xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1C(CH3), xe2x80x94CH2Cxe2x89xa1C(C6H5) xe2x80x94CH2CH2Cxe2x89xa1CH, xe2x80x94CH2CH2Cxe2x89xa1C(CH3), xe2x80x94CH2CH2Cxe2x89xa1C(C6H5) xe2x80x94CH2CH2CH2Cxe2x89xa1CH, xe2x80x94CH2CH2CH2Cxe2x89xa1C(CH3), xe2x80x94CH2CH2CH2Cxe2x89xa1C(C6H5) cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, cyclopentyl-CH2xe2x80x94, cyclohexyl-CH2xe2x80x94, (2-CH3-cyclopropyl)CH2xe2x80x94, (3-CH3-cyclobutyl)CH2xe2x80x94, cyclopropyl-CH2CH2xe2x80x94, cyclobutyl-CH2CH2xe2x80x94, cyclopentyl-CH2CH2xe2x80x94, cyclohexyl-CH2CH2xe2x80x94, (2-CH3-cyclopropyl)CH2CH2xe2x80x94, (3-CH3-cyclobutyl)CH2CH2xe2x80x94, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, furanyl-CH2xe2x80x94, thienyl-CH2xe2x80x94, pyridyl-CH2xe2x80x94, 1-imidazolyl-CH2xe2x80x94, oxazolyl-CH2xe2x80x94, isoxazolyl-CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, furanyl-CH2CH2xe2x80x94, thienyl-CH2CH2xe2x80x94, pyridyl-CH2CH2xe2x80x94, 1-imidazolyl-CH2CH2xe2x80x94, oxazolyl-CH2CH2xe2x80x94, isoxazolyl-CH2CH2xe2x80x94,
W is a bond;
X is a bond;
Y is a bond;
Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl;
R11, at each occurrence, is independently selected from H, xe2x95x90O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 3-CH3-phenyl, (3-CH3-phenyl)CH2xe2x80x94, (3-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, cyclohexyl, cycloheptyl, piperidinyl, or homopiperidinyl; and
R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94OCH3, or xe2x80x94CF3.
[11] In another preferred embodiment the present invention provides for a compound of Formula (Ib):
R3 and R3a are combined to form cyclobutyl, cyclopentyl, cyclopentenyl, or cyclohexyl;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, (2-CH3-cyclopropyl)CH2xe2x80x94, or (3-CH3-cyclobutyl)CH2xe2x80x94;
W is a bond;
X is a bond;
Y is a bond;
Z is methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, s-butyl, t-butyl, or allyl;
R11, at each occurrence, is independently selected from H, xe2x95x90O, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 3-CH3-phenyl, (3-CH3-phenyl)CH2xe2x80x94, (3-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, cyclohexyl, cycloheptyl, piperidinyl, or homopiperidinyl; and
R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94COCH3, or xe2x80x94CF3.
[12] In another preferred erbodiment the present invention provides for a compound. of Formula (Ib): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R3 and R3a are combined to form a 3-8 membered carbocyclic moiety;
wherein said 3-8 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-8 membered carbocyclic moiety is substituted with 0-3 R4;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, NR15R16, OR14a, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R5 is H;
C1-C6 alkyl substituted with 0-3 R5b;
C2-C6 alkenyl substituted with 0-3 R5b;
C2-C6 alkynyl substituted with 0-3 R5b;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5b, at each occurrence, is independently selected from:
H, C1-C6 alkyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16;
C3-C10 carbocycle substituted with 0-3 R5c;
C6-C10 aryl substituted with 0-3 R5c; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C7 carbocycle substituted with 0-3 R11b; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, pi.peridinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, C1-C4 alkyl, OR14, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-2 RXb;
C3-C6 cycloalkyl substituted with 0-2 RXb; or
5 to 6 membered heterocycle substituted with 0-2 RXb;
RXb, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O2xe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is C1-C3 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, C2-C6 alkoxyalkyl, or C3-C6 cycloalkyl;
R14a is H, phenyl, benzyl, or C1-C4 alkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)-S(xe2x95x90O)2xe2x80x94;
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, (C1-C4 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C4 alkyl)-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, C1-C6 alkyl, phenyl, benzyl, phenethyl, (C1-C6 alkyl)-C(xe2x95x90O)xe2x80x94, and (C1-C6 alkyl)-S(xe2x95x90O)2xe2x80x94;
R19, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19b, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl.
[13] In another preferred embodiment the present invention provides for a compound. of Formula (Ib) wherein:
R3 and R3a are combined to form a 3-6 membered carbocyclic moiety;
wherein said 3-6 membered carbocyclic moiety is saturated or partially unsaturated;
wherein said 3-6 membered carbocyclic moiety is substituted with 0-2 R4;
R4, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, CF3, acetyl, SCH3, methyl, ethyl, methoxy, ethoxy, allyl, xe2x80x94OCF3, and xe2x80x94SCF3;
R5 is H;
C1-C4 alkyl substituted with 0-3 R5b;
C2-C4 alkenyl substituted with 0-3 R5b; or
C2-C4 alkynyl substituted with 0-3 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, Cl, F, Br, I, xe2x95x90O;
C3-C6 carbocycle substituted with 0-3 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R5c;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C4 alkyl, C1-C3 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19, CF3;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
C3-C7 carbocycle substituted with 0-3 R11b; and
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, faranyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-1 RXb; or
5 to 6 membered heterocycle substituted with 0-1 RXb;
RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94;
Z is C1-C2 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, Br, I, CN, NO2, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4 haloalkyl-Sxe2x80x94;
R13, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C4 alkyl, or C2-C4 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, and benzyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, phenethyl, methyl-C(xe2x95x90O)xe2x80x94, ethyl-C(xe2x95x90O)xe2x80x94, methyl-S(xe2x95x90O)2xe2x80x94, and ethyl-S(xe2x95x90O)2xe2x80x94;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
[14] In another preferred embodiment the present invention provides for a compound of Formula (Ib) wherein:
R3 and R3a are combined to form a 3-6 membered carbocyclic moiety selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl; wherein said 3-6 membered carbocyclic moiety is substituted with 0-1 R4;
R4 is selected from H, OH, Cl, F, CN, CF3, methyl, ethyl, methoxy, ethoxy, allyl, and xe2x80x94OCF3;
R5 is C1-C4 alkyl substituted with 0-1 R5b;
C2-C4 alkenyl substituted with 0-1 R5b;
C2-C4 alkynyl substituted with 0-1 R5b;
R5b, at each occurrence, is independently selected from:
H, methyl, ethyl, propyl, butyl, CF3, OR14, xe2x95x90O;
C3-C6 carbocycle substituted with 0-2 R5c;
phenyl substituted with 0-3 R5c; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R5c; wherein said 5 to 6 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R5c, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
Ring B is selected from: 
R11, at each occurrence, is independently selected from H, xe2x95x90O, NR18R19;
C1-C4 alkyl optionally substituted with 0-1 R11a;
phenyl substituted with 0-3 R11b;
cyclohexyl substituted with 0-3 R11b;
cycloheptyl substituted with 0-3 R11b;
5 to 7 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 7 membered heterocycle is substituted with 0-3 R11b; wherein said 5 to 7 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, homopiperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl;
R11a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, phenoxy, F, Cl, xe2x95x90O, NR15R16, CF3, or phenyl substituted with 0-3 R11b;
R11b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy;
W is a bond or xe2x80x94CH2xe2x80x94;
X is a bond;
phenyl substituted with 0-1 RXb;
C3-C6 cycloalkyl substituted with 0-1 RXb; or
5 to 6 membered heterocycle substituted with 0-1 RXb;
RXb is selected from H, OH, Cl, F, NR15R16, CF3, acetyl, methyl, ethyl, methoxy, ethoxy, and xe2x80x94OCF3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94;
Z is C1-C2 alkyl substituted with 1-2 R12a;
C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-3 R12b; or
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b;
R12a, at each occurrence, is independently selected from C6-C10 aryl substituted with 0-4 R12b;
C3-C10 carbocycle substituted with 0-4 R12b; and
5 to 10 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 10 membered heterocycle is substituted with 0-3 R12b; and wherein said 5 to 10 membered heterocycle is selected from pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl;
R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
R13, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, Cl, F, Br, CN, NR15R16, and CF3;
R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl;
R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl;
R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and
R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
[15] In another preferred embodiment the present invention provides for a compound of Formula (Ib) wherein:
R3 and R3a are combined to form cyclobutyl, cyclopentyl, cyclopentenyl, or cyclohexyl;
R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH(CH3)CH2CH2CH3, xe2x80x94CH2CH(CH3)CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH(CH2CH3)2, cyclopropyl-CH2xe2x80x94, cyclobutyl-CH2xe2x80x94, (2-CH3-cyclopropyl)CH2xe2x80x94, or (3-CH3-cyclobutyl)CH2xe2x80x94;
W is a bond or xe2x80x94CH2xe2x80x94;
X is a bond; 
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94,
Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl)CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94, (thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, (cyclopropyl)CH2xe2x80x94, (cyclobutyl)CH2xe2x80x94, (cyclopentyl)CH2xe2x80x94, (cyclohexyl)CH2xe2x80x94, (morpholino)CH2xe2x80x94, (N-pipridinyl)CH2xe2x80x94, phenyl-CH2CH2xe2x80x94, (phenyl)2CHCH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, (2-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, (2,3-diF-phenyl)CH2CH2xe2x80x94, (2,4-diF-phenyl)CH2CH2xe2x80x94, (2,5-diF-phenyl)CH2CH2xe2x80x94, (2,6-diF-phenyl)CH2CH2xe2x80x94, (3,4-diF-phenyl)CH2CH2xe2x80x94, (3,5-diF-phenyl)CH2CH2xe2x80x94, (2,3-diCl-phenyl)CH2CH2xe2x80x94, (2,4-diCl-phenyl)CH2CH2xe2x80x94, (2,5-diCl-phenyl)CH2CH2xe2x80x94, (2,6-diCl-phenyl)CH2CH2xe2x80x94, (3,4-diCl-phenyl)CH2CH2xe2x80x94, (3,5-diCl-phenyl)CH2CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2CH2xe2x80x94, (2-MeO-phenyl)CH2CH2xe2x80x94, (3-MeO-phenyl)CH2CH2xe2x80x94, (4-MeO-phenyl)CH2CH2xe2x80x94, (2-Me-phenyl)CH2CH2xe2x80x94, (3-Me-phenyl)CH2CH2xe2x80x94, (4-Me-phenyl)CH2CH2xe2x80x94, (2-MeS-phenyl)CH2CH2xe2x80x94, (3-MeS-phenyl)CH2CH2xe2x80x94, (4-Mes-phenyl)CH2CH2xe2x80x94, (2-CF3O-phenyl)CH2CH2xe2x80x94, (3-CF3O-phenyl)CH2CH2xe2x80x94, (4-CF3O-phenyl)CH2CH2xe2x80x94, (furanyl)CH2CH2xe2x80x94, (thienyl)CH2CH2xe2x80x94, (pyridyl)CH2CH2xe2x80x94, (2-Me-pyridyl)CH2CH2xe2x80x94, (3-Me-pyridyl)CH2CH2xe2x80x94, (4-Me-pyridyl)CH2CH2xe2x80x94, (imidazolyl)CH2CH2xe2x80x94, (oxazolyl)CH2CH2xe2x80x94, (isoxazolyl)CH2CH2xe2x80x94, (benzimidazolyl)CH2CH2xe2x80x94, (cyclopropyl)CH2CH2xe2x80x94, (cyclobutyl)CH2CH2xe2x80x94, (cyclopentyl)CH2CH2xe2x80x94, (cyclohexyl)CH2CH2xe2x80x94, (morpholino)CH2CH2xe2x80x94, or (N-pipridinyl)CH2CH2xe2x80x94;
R11, at each occurrence, is independently selected from H, xe2x95x90O, methyl, ethyl, phenyl benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 3-CH3-phenyl, (3-CH3-phenyl)CH2xe2x80x94, (3-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, pyrid-3-yl, pyri1-4-yl, cyclohexyl, cycloheptyl, piperidinyl, or homopiperidinyl; and
R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94OCH3, or xe2x80x94CF3.
[16] In another preferred embodiment the present invention provides for a compound of Formula (Ic): 
or a pharmaceutically acceptable salt or prodrug thereof.
[17] In another preferred embodiment the present invention provides for a compound of Formula (Id): 
or a pharmaceutically acceptable salt or prodrug thereof.
[18] In another preferred embodiment the present invention provides for a compound of Formula (Ie): 
or a pharmaceutically acceptable salt or prodrug thereof.
[19] In another preferred embodiment the present invention provides for a compound of Formula (If): 
or a pharmaceutically acceptable salt or prodrug thereof.
[20] In another preferred embodiment the present invention provides for a compound of Formula (Ig): 
or a pharmaceutically acceptable salt or prodrug thereof.
[21] In another preferred embodiment the present invention provides for a compound of Formula (I) selected from:
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopentanecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclohexanecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclohexanecarboxylic amide;
1-[3-Methyl-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]-azepin-7-ylcarbamoyl)-butyl]-cyclohexanecarboxylic acid amide;
1-[3-Methyl-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]-azepin-7-ylcarbamoyl)-butyl]-cyclohexanecarboxylic acid amide;
1-(1-{1-[3-(2-Fluoro-phenoxy)-bienzyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl}-3-methyl-butyl)-cyclopent-3-enecarboxylic acid amide;
1-{3-Methyl-1-[2-oxo-1-(3-phenylamino-benzyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl]-butyl}-cyclopent-3-enecarboxylic acid amide;
1-{3-Methyl-1-[2-oxo-1-(3-phenylamino-benzyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl]-butyl}-cyclopentanecarboxylic acid amide;
1-[2-Cyclopropyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-ethyl]-cyclopent-3-enecarboxylic amide;
1-[2-Cyclopropyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(2-trifluoromethylphenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-ethyl]-cyclopent-3-enecarboxylic amide;
1-[2-Cyclopropyl-1-(5-methyl-6--oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl]-cyclopent-3-enecarboxylic acid amide;
1-{3-Methyl-1-[2-oxo-1-(3-o-tolylamino-benzyl)-azepan-3-ylcarbamoyl]-butyl}-cyclopent-3-enecarboxylic acid amide;
1-[3-Methyl-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-butyl]-cyclopent-3-enecarboxylic acid amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide;
1-[3-Methyl-1-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-butyl]-cyclopentanecarboxylic acid amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopentanecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro1--methyl-2-oxo-5-(4-trifluoromethylphenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cylopent-3-enecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-(i-propyl)-2-oxo-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(4-trifluoromethyiphenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopentanecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-(2-cyclopropylethyl)-2-oxo-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-(2-methylpropyl) )-2-oxo-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclobutanecarboxylic amide;
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclobutanecarboxylic amide; and
1-[3-methyl-1-[1,3-dihydro-1-methyl-2-oxo-5-cycloheptyl-2H-1,4-benzodiazepin-3-ylcarbamoyl]-butyl]-cyclopent-3-enecarboxylic amide.
In a more preferred embodiment of the present invention, Q is NH2.
It is appreciated that certain features of the invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. As such, it is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional embodiments of the present invention. Conversely, various features of the invention which are for brevity, described herein in the context of a single embodiment, may also be provided separately or in any subcombination. As such, it is understood that any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
In a preferred embodiment Ring B is selected from: 
In another preferred embodiment Ring B is selected from: 
In another preferred embodiment Ring B is singly: 
In another preferred embodiment Ring B is singly: 
Also included in the present invention are compounds as set forth in the embodiments above wherein R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; and R5 and R5a are not combined to form a 3-8 membered carbocyclic moiety.
Also included in the present invention are compounds as set forth in the embodiments above wherein R3 and R3a are not combined to form a 3-8 membered carbocyclic moiety; and R5 and R5a are combined to form a 3-8 membered carbocyclic moiety;
Also included in the present invention are compounds as set forth in the embodiments above wherein R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; and R5 and R5a are also combined to form a 3-8 membered carbocyclic moiety.
Also included in the present invention are compounds as set forth in the embodiments above wherein R3 and R3a are combined to form a 3-8 membered carbocyclic moiety which is saturated or partially unsaturated.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety selected from, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.
In another preferred embodiment R3 and R3a are combined to form a cyclobutyl moiety.
In another preferred embodiment R3 and R3a are combined to form a cyclopentyl moiety.
In another preferred embodiment R3 and R3a are combined to form a cyclopentenyl moiety.
In another preferred embodiment R3 and R3a are combined to form a cyclohexyl moiety.
Also included in the present invention are compounds as set forth in the embodiments above wherein R5 and R5a are combined to form a 3-8 membered carbocyclic moiety which is saturated or partially unsaturated.
In another preferred embodiment R5 and R5a are combined to form a 3-8 membered carbocyclic moiety selected from, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.
In another preferred embodiment R5 and R5a are combined to form a cyclobutyl moiety.
In another preferred embodiment R5 and R5a are combined to form a cyclopentyl moiety.
In another preferred embodiment R5 and R5a are combined to form a cyclopentenyl moiety.
In another preferred embodiment R5 and R5a are combined to form a cyclohexyl moiety.
Also included in the present invention are compounds as set forth in the embodiments above wherein R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or (C3-C6 cycloalkyl)C1-C3 alkyl-; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is C1-C6 alkyl, C2-C6 alkenyl, or (C3-C6 cyclo-alkyl)C1-C3 alkyl-; and R5a is H.
In three more preferred embodiments R3 and R3 are combined to form a 3-8 membered carbocyclic moiety; R5 is C1-C6 alkyl or C2-C6 alkenyl or (C3-C6 cycloalkyl)C1-C3 alkyl-; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is C1-C4 alkyl, C2-C4 alkenyl, or (C3-C6 cycloalkyl)C1-C2 alkyl-; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is methyl, ethyl, propyl, butyl, allyl, cyclopropylmethyl, cyclobutylmethyl, or cyclohexylmethyl; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is ethyl, propyl, butyl, allyl, or cyclopropylmethyl; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, allyl, or cyclopropylmethyl; and R5a is H.
In another preferred embodiment R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is n-butyl, i-butyl, or cyclopropylmethyl; and R5a is H.
In more preferred embodiments R3 and R3a are combined to form a 3-8 membered carbocyclic moiety; R5 is methyl or ethyl or propyl or butyl or allyl or cyclopropylmethyl or cyclobutylmethyl or cyclohexylmethyl; and R5a is H.
Also included in the present invention are compounds as set forth in the embodiments above wherein R5 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or (C3-C6 cycloalkyl)C1-C4 alkyl, (NR15R16)C1-C4 alkyl.
In another preferred embodiment R5 is C2-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl.
In another preferred embodiment R5 is C3-C8 alkyl, C3-C8 alkenyl, or C3-C8 alkynyl.
In another preferred embodiment R5 is C4-C8 alkyl, C4-C8 alkenyl, C4-C8 alkynyl.
In another preferred embodiment R5 is C2-C8 alkyl. In another preferred embodiment R5 is C3-C8 alkyl. In another preferred embodiment R5 is C4-C8 alkyl. In another preferred embodiment R5 is (C3-C6 cycloalkyl)C1-C4 alkyl. In another preferred embodiment R5 is (NR15R16)C1-C4 alkyl.
In another preferred embodiment R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH(CH3)2, xe2x80x94CH2NH2, xe2x80x94CH2N(CH3)2, xe2x80x94CH2N(CH2CH3)2, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2CH2N(CH2CH3)2, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclopentyl, or xe2x80x94CH2-cyclohexyl.
In another preferred embodiment R5 is xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94CH2CH2CH3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH2CH2CH2CH3, xe2x80x94CH2CH2CH2CH(CH3)2, or xe2x80x94CH2CH2CH2CH2CH(CH3)2.
In another preferred embodiment R5 is xe2x80x94CH2NH2, xe2x80x94CH2N(CH3)2, xe2x80x94CH2N(CH2CH3)2, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2N(CH3)2, or xe2x80x94CH2CH2N(CH2CH3)2.
In another preferred embodiment R5 is xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclopentyl, or xe2x80x94CH2-cyclohexyl.
Also included in the present invention are compounds as set forth in the embodiments above wherein R6 is H.
Also included in the present invention are compounds as set forth in the embodiments above wherein R11 is H, NR18R19; C1-C4 alkyl optionally substituted with 0-1 R11a; phenyl substituted with 0-3 R11b; C3-C7 cycloalkyl substituted with 0-3 R11b; or pyridinyl substituted with 0-3 R11b;
wherein R11a is phenyl substituted with 0-3 R11b; wherein R11b, at each occurrence, is independently selected from H, OH, Cl, F1, CF3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, and propoxy.
In another preferred embodiment R11 is independently selected from H, methyl, ethyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, phenethyl, 4-F-phenyl, (4-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2CH2xe2x80x94, 3-F-phenyl, (3-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2CH2xe2x80x94, 2-F-phenyl, (2-F-phenyl)CH2xe2x80x94, (2-F-phenyl)CH2CH2xe2x80x94, 4-Cl-phenyl, (4-Cl-phenyl)CH2xe2x80x94, (4-Cl-phenyl)CH2CH2xe2x80x94, 3-Cl-phenyl, (3-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2CH2xe2x80x94, 4-CH3-phenyl, (4-CH3-phenyl)CH2xe2x80x94, (4-CH3-phenyl)CH2CH2xe2x80x94, 3-CH3-phenyl, (3-CH3-phenyl)CH2xe2x80x94, (3-CH3-phenyl)CH2CH2xe2x80x94, 4-CF3-phenyl, (4-CF3-phenyl)CH2xe2x80x94, (4-CF3-phenyl)CH2CH2xe2x80x94, pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 4-CH3-pyrid-2-yl, 4-CF3-pyrid-2-yl, pyrid-3-yl, 4-F-pyrid-3-yl, 4-Cl-pyrid-3-yl, 4-CH3-pyrid-3-yl, 4-CF3-pyrid-3-yl, and pyrid-4-yl.
In another preferred embodiment R11 is independently selected from H, methyl, ethyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 4-CH3-phenyl, 3-CH3-phenyl, 4-CF3-phenyl, pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 4-CH3-pyrid-2-yl, and 4-CF3-pyrid-2-yl.
In another preferred embodiment. R11 is independently selected from phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 4-Cl-phenyl, 3-Cl-phenyl, 4-CH3-phenyl, 3-CH3-phenyl, and 4-CF3-phenyl.
In another preferred embodiment, R11 is independently selected from cyclopentyl, cyclohexyl, and cycloheptyl.
In another preferred embodiment R11 is independently selected from pyrid-2-yl, 4-F-pyrid-2-yl, 4-Cl-pyrid-2-yl, 4-CH3-pyrid-2-yl, and 4-CF3-pyrid-2-yl.
Also included in the present invention are compounds as set forth in the embodiments above wherein W may be selected from a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, or xe2x80x94CH(CH3)xe2x80x94.
In another preferred embodiment W is a bond or xe2x80x94(CH2)pxe2x80x94. In another preferred embodiment W is a bond, xe2x80x94CH2xe2x80x94, or xe2x80x94CH2CH2xe2x80x94. In another preferred embodiment W is a bond or xe2x80x94CH2xe2x80x94. In another preferred embodiment W is xe2x80x94CH2xe2x80x94. In another preferred embodiment W is a bond.
Also included in the present invention are compounds as set forth in the embodiments above wherein the integer p may be selected from 0, 1, 2, or 3.
In another preferred embodiment the integer p is 0, 1 or 2. In another preferred embodiment the integer p is 0 or 1. In another preferred embodiment the integer p is 0.
Also included in the present invention are compounds as set forth in the embodiments above wherein X is a bond, C6-C10 aryl, C3-C10 carbocycle or 5 to 10 membered heterocycle.
In another preferred embodiment X is a bond, phenyl, C3-C6 carbocycle, or 5 to 6 membered heterocycle.
In another preferred embodiment X is a bond, phenyl, C3-C6 cycoalkyl, or 5 to 6 membered heterocycle.
In another preferred embodiment X is a bond; 
In another preferred embodiment X is a bond; 
In another preferred embodiment X is a bond or phen-1,3-diyl. In another preferred embodiment X is phen-1,3-diyl. In another preferred embodiment X is a bond.
Also included in the present invention are compounds as set forth in the embodiments above wherein Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94N(R19)xe2x80x94, C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94.
In another preferred embodiment Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94NHC(xe2x95x90O)xe2x80x94, xe2x80x94NHS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NHxe2x80x94, xe2x80x94NHS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NHxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94.
In another preferred embodiment Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, or xe2x80x94N(CH2CH3)xe2x80x94.
In another preferred embodiment Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94.
In another preferred embodiment Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(CH3)xe2x80x94. In another preferred embodiment Y is xe2x80x94Oxe2x80x94. In another preferred embodiment Y is xe2x80x94NHxe2x80x94. In another preferred embodiment Y is xe2x80x94N(CH3)xe2x80x94. In another preferred embodiment Y is a bond.
Also included in the present invention are compounds as set forth in the embodiments above wherein Z is
C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C2 alkyl substituted with 1-2 R12a;
phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-3 R12b; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b;
wherein R12a is phenyl substituted with 0-4 R12b;
C3-C6 carbocycle substituted with 0-4 R12b; or
5 to 6 membered heterocycle containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur, wherein said 5 to 6 membered heterocycle is substituted with 0-3 R12b; and
wherein R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O) CH3, S( xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
In another preferred embodiment Z is
C1-C2 alkyl substituted with 1-2 R12a; or
phenyl substituted with 0-4 R12b;
wherein R12a is phenyl substituted with 0-4 R12b;
wherein R12b, at each occurrence, is independently selected from H, OH, Cl, F, NR15R16, CF3, acetyl, SCH3, S(xe2x95x90O)CH3, S(xe2x95x90O)2CH3, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, and xe2x80x94OCF3;
In another preferred embodiment Z is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl.
In another preferred embodiment Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, furanyl, thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl, 1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl, phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-(Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH2xe2x80x94, (3-MeO-phenyl) CH2xe2x80x94, (4-MeO-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me-phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, (furanyl)CH2xe2x80x94, (thienyl)CH2xe2x80x94, (pyridyl)CH2xe2x80x94, (2-Me-pyridyl)CH2xe2x80x94, (3-Me-pyridyl)CH2xe2x80x94, (4-Me-pyridyl)CH2xe2x80x94, (1-imidazolyl)CH2xe2x80x94, (oxazolyl)CH2xe2x80x94, (isoxazolyl)CH2xe2x80x94, (1-benzimidazolyl)CH2xe2x80x94, (cyclopropyl)CH2xe2x80x94, (cyclobutyl)CH2xe2x80x94, (cyclopentyl)CH2xe2x80x94, (cyclohexyl)CH2xe2x80x94, (morpholino)CH2xe2x80x94, (N-pipridinyl)CH2xe2x80x94, or (phenyl)2CHxe2x80x94.
In another preferred embodiment Z is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me--phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, 4-CF3O-phenyl, or 4-phenyl-phenyl.
In another preferred embodiment Z is phenyl-CH2xe2x80x94, (2-F-phenyl)CH2xe2x80x94, (3-F-phenyl)CH2xe2x80x94, (4-F-phenyl)CH2xe2x80x94, (2-Cl-phenyl)CH2xe2x80x94, (3-Cl-phenyl)CH2, (4-Cl-phenyl)CH2xe2x80x94, (2,3-diF-phenyl)CH2xe2x80x94, (2,4-diF-phenyl)CH2xe2x80x94, (2,5-diF-phenyl)CH2xe2x80x94, (2,6-diF-phenyl)CH2xe2x80x94, (3,4-diF-phenyl)CH2xe2x80x94, (3,5-diF-phenyl)CH2xe2x80x94, (2,3-diCl-phenyl)CH2xe2x80x94, (2,4-diCl-phenyl)CH2xe2x80x94, (2,5-diCl-phenyl)CH2xe2x80x94, (2,6-diCl-phenyl)CH2xe2x80x94, (3,4-diCl-phenyl)CH2xe2x80x94, (3,5-diCl-phenyl)CH2xe2x80x94, (3-F-4-Cl-phenyl)CH2xe2x80x94, (3-F-5-Cl-phenyl)CH2xe2x80x94, (3-Cl-4-F-phenyl)CH2xe2x80x94, (2-MeO-phenyl)CH22xe2x80x94, (3-MeO-phernyl)CH2xe2x80x94, (4-Meo-phenyl)CH2xe2x80x94, (2-Me-phenyl)CH2xe2x80x94, (3-Me -phenyl)CH2xe2x80x94, (4-Me-phenyl)CH2xe2x80x94, (2-MeS-phenyl)CH2xe2x80x94, (3-MeS-phenyl)CH2xe2x80x94, 4-MeS-phenyl)CH2xe2x80x94, (2-CF3O-phenyl)CH2xe2x80x94, (3-CF3O-phenyl)CH2xe2x80x94, (4-CF3O-phenyl)CH2xe2x80x94, or (phenyl)2CHxe2x80x94.
Also included in the present invention are compounds as set forth in the embodiments above wherein R13, at each occurrence, is independently selected from H, F, Cl, OH, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94OCH3, and xe2x80x94CF3.
Also included in the present invention are compounds as set forth in the embodiments above wherein R14 is H, phenyl, benzyl, methyl, ethyl, propyl, or butyl;
Also included in the present invention are compounds as set forth in the embodiments above wherein R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
Also included in the present invention are compounds as set forth in the embodiments above wherein R16, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
Also included in the present invention are compounds as set forth in the embodiments above wherein R18, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, phenyl, benzyl, and phenethyl.
Also included in the present invention are compounds as set forth in the embodiments above wherein R19, at each occurrence, is independently selected from H, methyl, ethyl, propyl, and butyl.
In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with xcex2-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
In a preferred embodiment the neurological disorder associated with xcex2-amyloid production is Alzheimer""s Disease.
In a fourth embodiment, the present invention provides a method for inhibiting xcex3-secretase activity for the treatment of a physiological disorder associated with inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibit-on a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
Thus, the present invention provides a method for inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
In a preferred embodiment the physiological disorder associated with inhibiting xcex3-secretase activity is Alzheimer""s Disease.
In a fifth embodiment, the present invention provides a compound of Formula (I) for use in therapy.
In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer""s Disease.
In a sixth embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer""s Disease.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is:
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2 amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex2 secretase, generating the N-terminus of Axcex2, xcex1 secretase cleaving around. the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e. xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g. R5b) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R5b, then said group may optionally be substituted with up to two R5b groups and R5b at each occurrence is selected independently from the definition of R5b. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group, unless otherwise specified, is xe2x80x9cC1-C4 alkylxe2x80x9d. Additionally, unless otherwise specified, xe2x80x9cpropylxe2x80x9d denotes n-propyl or i-propyl; xe2x80x9cbutylxe2x80x9d denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxylxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxylxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms: attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenryl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred xe2x80x9ccarbocyclexe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, xe2x80x9ccarbocyclic moietyxe2x80x9d is intended to mean any stable 3- to 8-membered monocyclic ring of carbon atoms, any of which may be saturated or partially unsaturated. Additionally, the 3 to 8 membered monocyclic ring of carbon atoms may be contain a heteroatom selected from oxygen, sulphur, or nitrogen, wherein a carbon atom of the ring has been substituted for the heteroatom. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopent-3-enyl, cyclohex-3-enyl, tetrahydrofurnayl, pyranyl, pyrrolidinyl, and piperidinyl. Preferred examples of a xe2x80x9ccarbocyclic moietyxe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl. phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidtinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred xe2x80x9carylxe2x80x9d is phenyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, or C1-C4 haloalkyl.
As used herein, the term xe2x80x9cheteroaryl fused radicalxe2x80x9d is intended to denote a 5 or 6 membered aromatic ring comprising carbon atoms and one or two heteroatoms selected from nitrogen, sulphur and oxygen. The 5 or 6 membered ring is fused to two adjacent atoms of a second ring wherein the second ring is a xe2x80x9ccarbocyclic moietyxe2x80x9d or ring B as defined above. Examples of a xe2x80x9cheteroaryl fused radicalxe2x80x9d are furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, thiophenyl, thiazolyl, isothiozalyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
The phrase xe2x80x9cadditional lactam carbonsxe2x80x9d, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring B of Formula (I). Formula (Ixe2x80x3): 
represents the lactam ring B of Formula (I). Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. It is further understood that lactam ring B may optionally be unsaturated or partially unsaturated (i.e. two adjacent atoms in the ring form a double bond) wherein the backbone of lactam ring B may contain one, two or three double bonds. Examples of lactam ring B include: 
but are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R10 or R11 on lactam B are hydrogen, methyl, ethyl, phenyl, benzyl, phenethyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-CF3-phenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-methylphenyl)methyl, (4-CF3-phenyl)methyl, (4-fluorophenyl ethyl, (4-chlorophenyl)ethyl, (4-methylphenyl)ethyl, (4-CF3-phenyl)ethyl, and 2-, 3-, and 4-pyridinyl. More preferred examples of substituent R10 or R11 on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-CF3-phenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, (4-CF3-phenyl)methyl, and 2-, 3-, and 4-pyridinyl. Preferred examples of R13 on lactam B are F, Cl, OH, methyl, ethyl, methoxy, and trifluoromethyl.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (Ixe2x80x3) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (Ixe2x80x3) is considered part of the invention. An example of such configuration includes, the S isomer: 
and the R isomer: 
but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atoms to which R3 and R5, are attached may describe chiral carbons which may display superior biological activity over the opposite enantiomer. For example, where and R5 is not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vitro when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
Methods for the synthesis of succinylamino lactams are known in the art and are disclosed in a number of references including PCT publication number WO 96/29313, which is hereby incorporated by reference. 
Compounds of the present invention can be prepared by an amino acid coupling procedure. An example of the synthetic method employed to prepare compounds of the present invention is illustrated in the amino acid coupling of succinate derivative XI and lactam XII to give a compound of Formula II as shown in Scheme 1. It is understood that ring C represents variables R3 and R3a of Formula (I). The cyclic succinate derivative XI can be prepared from a mono-ester succinate derivative X which can be prepared from the corresponding diester or acid.
Examples of succinates wherein ring C is a carbocyclic or heterocyclic system are well known in the literature. For example, a dimethyl succinate having a 3-membered cyclopropyl ring C can be formed by a thermal or photolytic decomposition of a methyl 3(carbomethoxymethyl)-1-pyrazoline-3-carboxylate. See Bull. Soc. Chim. Fr. (1971), (6), 2290-5. A succinic acid derivative wherein ring C is a 4-membered cyclobutyl group can be formed by the method published in U.S. Pat. No. 3,828,025. A succinic acid derivative wherein ring C is a 5-membered cyclopentyl group can be formed using the methods described in Le Moal, H. et al., Bull. Soc. Chim. Fr., 1964, 579-584; Borenstein, M. R., et al., Heterocycles, 22, 1984, 2433-2438. Other examples of derivatives of succinate X wherein ring C is a five-membered cyclopentyl group or a 6-membered cyclohexyl group have been employed as matrix matalloproteinase inhibitors. See Bioorg. Med. Chem. Lett. (1998), 8(12), 1443-1448; Robinson, R. P., et al., Bioorg. Med. Chem. Lett. (1996), 6(14), 1719-1724. For the preparation of a succinic acid wherein ring C is an oxygen containing 3-membered oxirane see Kirshenbaum, K. S., Sharpless, K. B., J. Org. Chem. (1985), 50(11), 1979-82. For examples of succinate derivatives wherein ring C is a 5- or 6-membered heterocycle ring see Olivero, S., Dunach, E., Eur. J. Org. Chem. (1999), (8), 1885-1891; Eckardt et al. Helv. Chim. Acta, 55, 1972, 2432, 2433, 2434, 2438; Sandoz Ltd., NL 6409801 1963, Chem. Abstract., 63, 1965, 8324d; and Rice, L. M., et al., J. Med. Chem., 6, 1963, 388-402. It is understood that these references are only illustrative of the availability of some carbocyclic and heterocyclic succinates, however numerous references are known in literature which provide preparations of other substituted carbocyclic and heterocyclic succinates and their derivatives.
Scheme 2 illustrates one method for the introduction of a substitution on a carbon adjacent to the cyclic group in succinate IX via a deprotonation followed by standard alkylation procedures known to one skilled in the art. Treatment of IX with a base followed by addition of an R5-LG, wherein LG is a leaving group such as a halide, mesylate, triflate or a tosylate, and subsequent deprotection of the benzyl group by hydrogenation employing, for example, H2 and Pd/C, would give the desired succinate X. 
An example of a general method whereby diesters of structure IX can be obtained from cyclic esters XXX is shown in Scheme 2a. Deprotonation of such esters with, for example LDA or lithium hexamethyldisilazide, followed by reaction of the resulting ester enolate with allyl bromide provides allyl esters XXXI, which may be oxidized using ruthenium peroxide in the presence of sodium periodate to give free acids XXXII. If desired, esterification may be carried out using e.g. benzyl bromide in the presence of potassium carbonate.
Succinate acids such as XXXV with defined stereochemistry may be prepared from cyclic mono-acids XXXIII by use of a chiral auxiliary such as an oxazolidinone, as shown in Scheme 2b. Thus, acid XXXIII may be converted to the oxazolidinone XXXIV and subjected to the Evans stereospecific alkylation sequence to provide, after removal of the auxiliary, acid esters XXXV. Suitable alkylating agents include alkyl, allyl, propenyl or benzyl iodides or triflates, as is known to those skilled in the art. Use of the appropriate stereochemistry in the chiral auxiliary can provide substituted cyclic succinates of either absolute configuration. 
An example of a class of compounds compound which can be prepared according to the general methods described above is shown in Scheme 3. In step 1, cyclopentyl succinate X-a is converted to cyclopentyl succinamide XI-a. The subsequent amino acid coupling between succimamide XI-a and a benzodiazepine 11 under standard coupling conditions known to one skilled in the art would give the product III.
In the preparation of a compound of Formula I, in some cases it may be desirable to perform the coupling of an amino lactam and a succinic acid derivative prior to the amidation of the succinic acid compound. In Scheme 4 the coupling of a benzodiazepine 11 and the succinic acid derivative 10 is performed first to give the coupled product 12. Subsequent conversion of the ester function to an amide can be done by a deprotection step followed by an amino acid coupling step using standard coupling conditions to give a compound 13. 
A variation of the coupling procedure of Scheme 4 useful in the synthesis of compounds of the present invention is illustrated in Scheme 4a, and involves conversion of the acid ester 10 to the corresponding HOBt ester using standard procedures, such as EDC/HOBt. In a separate step, the activated ester XL is allowed to react with a lactam amine XLI in a suitable solvent, such as DMF, preferably with warming of the reaction mixture to 40-100xc2x0 C. As will be recognized by those skilled in the art, a variety of procedures for the synthesis of amides from carboxylic acids are known (see, for example, Peptide Synthesis Protocols, ed. by M. W. Pennington and B. M. Dunn, Methods in Molecular Biology, Vol. 35, Humana Press, 1994; and Comprehensive Organic Functional Group Transformations, ed. by A. R. Katritzky, O. Meth-Cohn, C. W. Rees, Volume 5, pp 274-281 [P. D. Bailey, I. D. Collier and K. M. Morgan, Amides], Pergamon, 1995), and the skilled practitioner will adjust the methods, reagents and conditions to the example at hand.
The methods illustrated above may be modified to prepare cyclic succinoyl lactams where R5 and R5a comprise a cyclic group as shown in Scheme 4b. Thus the free acid of succinate esters prepared using the methods of Schemes 2, 2a or 2b may be suitably protected and the ester deprotected. Coupling of the free acid with an aminolactam may be carried out as described, and the remaining ester group converted to the desired amide. 
Compounds of the present invention in which R3 and R3a, and R5 and R5a comprise two cyclic groups may be prepared from the corresponding cyclic succinates as shown in Scheme 4c. Bis(cyclic) succinates useful in the preparation of intermediates represented by xx are available using the methods of Overberger et al. (J. Org. Chem. 1955, 20, 1717-1720) and Belletire et al. (Tet. Lett. 1984, 25, 5969-5972). 
Methods for the synthesis of lactams XI of Scheme 1 as contemplated by the present invention in lactam ring B of Formula (I), including amino benzodiazepinones, dibenzo azepinones and other related heterocycles, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, WO 99/66934, and WO 00/07995, which are hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239; Sherrill et al, J. Org. Chem., 1995, 60, 730-734; and Walsh, D. A., Synthesis, September 1980, p.677; and Brown, et al., Tetrahedron Letters, 1971, 8, 667-670.
An example of an L-xcex1-amino-xcex2-thio-xcex5-caprolactam, as shown in Scheme 5, where ring B is the amino lactam of XIII and J is a sulfur atom has been reported in the literature. See S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9. One skilled in the art can extend this methodology to the synthesis of xcex2-amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art. 
An approach to preparing representative compounds of Formula (I) is illustrated for caprolactam 20 in Scheme 6. The lactam nitrogen of intermediate 15 can be alkylated by generating the anion with bases, such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride, in solvents such as THF, with or without cosolvents such as DMPU or HMPA and reacting this with a variety of groups containing leaving groups (LG) for example, bromide, iodide, mesylate or tosylate. Alkylating agents such as alpha-bromo amides, ketones and acids, if not commercially available, can be prepared by a number of literature methods including halogenation of amino acids by diazotization. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed from a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to one skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347 and 695-698.
The N-Boc protecting group of caprolactam 16 can be removed by any number of methods well known in the literature, for example TFA in methylene chloride, to give the intermediate 17. The amine 17 can be coupled to an appropriately substituted carboxylic acid X-a, acid 
chloride or other activated acid derivative by methods well described in the literature for making amide bonds, for example, TBTU in DMF with a base such as NMM, to give the elaborated caprolactam 18. Optionally, caprolactam 18 can be alkylated using standard bases, such as LDA, NaH, or NaHMDS, to deprotonate the amide hydrogen followed by addition of an alkylating agent with an appropriate leaving group, such as halide, mesylate, or triflate in an appropriate solvent to provide an N-R6 alkylated product of caprolactam 18. The t-butyl carboxyl protecting group of the N-R6 alkylated product of caprolactam 18 can be removed, for example, by treatment with TFA in methylene chloride to give a carboxylic acid 19.
The final product 20 can be prepared by treating an activated carboxylic acid derivative of 19 with an appropriately substituted amine HNR1R2. For instance, activation of the carboxylic acid with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) or other coupling agents known to those skilled in the art allows condensation with ammonia to form primary amides. Similarly, condensation of the activated acid with hydroxylamine hydrochloride provides the hydroxamic acid, or reaction with a primary or secondary amine provides the substituted amine derivative. For additional acylation reactions see, for example, Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.
A different synthetic route to compounds of the present invention is shown in Scheme 7, step 1-5. In the method of Scheme 7, cyclization of two succinate substituents is carried out after coupling of the aminolactam and a suitable succinic acid derivative. In step 1, the amino lactam XII is coupled to an appropriately substituted succinate derivative XIV (n is 1, 2 or 3) or acid chloride by methods well described in the literature for making amide bonds, for example, TBTU in DMF with a base, for example, NNM to give the elaborated compound XV. 
The protecting group of the carboxyl group can be removed using standard deprotection methods to provide compound XVI. A subsequent second amino acid coupling with an amine NHR1R2 provides compound XVII which undergoes a ring-closing-metathesis to form a compound of formula IV in the presence of Ruthenium complexes using the method described by Grubbs and coworkers, J. Am. Chem. Soc., 114, 7324 (1992). Reduction of the cycloalkene of IV to a compound of formula V can be done using hydrogen or a hydrogen transfer reagent with Palladium as a catalyst or other reduction methods well known in the art.
The compound XIV of Scheme 7 can be prepared by a number of known procedures. See D. A. Evans et al, Org. Synth. 86, p83 (z1990) and P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138. The preparation of diastereomerically pure succinate XXI is outlined in Scheme 8 where acylation of an oxazolidinone with an acylating agent such as an acid chloride ClCOCH2R5 provides structure XVIII. Alkylation of XVIII with a BrCH2CO2t-Bu provides XIX followed by cleavage of the chiral auxiliary to give carboxylic acid XX. Subsequent alkylations of XX provides a variety of disubstituted succinate XXI which can be further alkylated to give a compound of formula XIV. 
An example of diastereomerically pure succinate derivative XIV employing a method of Scheme 8 in its preparation is outlined in Scheme 9, adapted from P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein by reference. This reference provides the synthesis shown below to obtain compound 24. Additional methods useful for the preparation of succinate derivatives are known by those skilled in the art. Such references include McClure and Axt, Bioorganic and Medicinal Chemistry Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of WO97/18207 and WO 98/51665 are hereby incorporated by reference. A further alkylation of disubstituted succinates such as XXI and 24 provides intermediates such as 25 useful as substrates, after esterification, for cyclization reactions known to one skilled in the art, such as ring closing metathesis (RCM) reactions using Grubbs"" catalyst as illustrated in Scheme 9. It will be appreciated by those skilled in the art that the analogous preparation of other cyclization substrates and the use of alternative ring forming methodologies will provide access to carbo- and heterocyclic analogs of intermediates 26 and 27. Such strategies include oxidative olefin cleavage using, for example, ozonolysis, followed by reduction to the corresponding diols, mono-activation with tosyl chloride, and cyclization to oxygen containing heterocycles using base. Treatment of dialdehydes with primary amines in the presence of sodium borohydride may be used to provide analogous nitrogen heterocyclic intermediates useful in the preparation of nitrogen heterocycles of Formula (I). The use of cycloalkylidene succinates such as 27 in the preparation of compounds of Formula (I) is illustrated in Schemes 7 and 10. 
The preparation of compounds 32 and 33 using the methods of Scheme 7 is shown in Scheme 10. The succinate product 29 is obtained from an amino acid coupling of a diallyl succinate 28 with a benzodiazepine 11 using a standard coupling procedure (HATU, DIEA, DMF). The carboxyl protecting group BOC is removed in TFA/CH2Cl2 to give a carboxylic acid 30. A second amino acid coupling of carboxylic acid 30 with ammonia in the presence of HATU and DIEA in DMF provides a diallyl succinate 31. A ring-closing-metathesis using a catalytic amount of Cl2Ru(PCy3)2(CHC6H6) as the metal carbene compound gives the cyclized product 32. Compound 33 is obtained from compound 32 by a hydrogen transfer reduction with Pd(OH)2/C and 1,4-cyclohexadiene in methanol. 
The amide hydrogen of a compound of formula VI can be deprotonated using standard bases, for example LDA, NaH, or NaHMDS, followed by addition of an alkylating agent R6-LG wherein LG is an appropriate leaving group, for example halide, mesylate, or triflate, in an appropriate solvent to provide a compound of formula VII, see Scheme 11. A similar synthetic sequence may be applied to protected intermediate XV, which may then be converted to VII using the methods described above. 
All references cited herein, are hereby incorporated by reference in their entirety unless otherwise stated.